Local Anesthetics

Local Anesthetics
Local anesthetics reversibly inhibit impulse
generation and propagation in
nerves. In sensory nerves, such an effect
is desired when painful procedures
must be performed, e.g., surgical or dental
operations.
Mechanism of action. Nerve impulse
conduction occurs in the form of
an action potential, a sudden reversal in
resting transmembrane potential lasting
less than 1 ms. The change in potential
is triggered by an appropriate stimulus
and involves a rapid influx of Na+
into the interior of the nerve axon.
This inward flow proceeds through a
channel, a membrane pore protein, that,
upon being opened (activated), permits
rapid movement of Na+ down a chemical
gradient ([Na+]ext ~ 150 mM, [Na+]int
~ 7 mM). Local anesthetics are capable
of inhibiting this rapid inward flux of
Na+; initiation and propagation of excitation
are therefore blocked .
Most local anesthetics exist in part
in the cationic amphiphilic form (cf).
This physicochemical property favors
incorporation into membrane
interphases, boundary regions between
polar and apolar domains. These are
found in phospholipid membranes and
also in ion-channel proteins. Some evidence
suggests that Na+-channel blockade
results from binding of local anesthetics
to the channel protein. It appears
certain that the site of action is reached
from the cytosol, implying that the drug
must first penetrate the cell membrane.

Local anesthetic activity is also
shown by uncharged substances, suggesting
a binding site in apolar regions
of the channel protein or the surrounding
lipid membrane.
Mechanism-specific adverse effects.
Since local anesthetics block Na+
influx not only in sensory nerves but also
in other excitable tissues, they are
applied locally and measures are taken
to impede their distribution
into the body. Too rapid entry into the
circulation would lead to unwanted
systemic reactions such as:
! blockade of inhibitory CNS neurons,
manifested by restlessness and seizures
(countermeasure: injection of a
Benzodiazepine ); general paralysis
with respiratory arrest after
higher concentrations.
! blockade of cardiac impulse conduction,
as evidenced by impaired AV
conduction or cardiac arrest (countermeasure:
injection of epinephrine).
Depression of excitatory processes
in the heart, while undesired
during local anesthesia, can be put to
therapeutic use in cardiac arrhythmias.

Forms of local anesthesia. Local
anesthetics are applied via different
routes, including infiltration of the tissue
(infiltration anesthesia) or injection
next to the nerve branch carrying
fibers from the region to be anesthetized
(conduction anesthesia of the
nerve, spinal anesthesia of segmental
dorsal roots), or by application to the
surface of the skin or mucosa (surface
anesthesia). In each case, the local anesthetic
drug is required to diffuse to
the nerves concerned from a depot
placed in the tissue or on the skin.
High sensitivity of sensory nerves,
low sensitivity of motor nerves. Impulse
conduction in sensory nerves is
inhibited at a concentration lower than
that needed for motor fibers. This difference
may be due to the higher impulse
frequency and longer action potential
duration in nociceptive, as opposed to
motor, fibers.
Alternatively, it may be related to
the thickness of sensory and motor
nerves, as well as to the distance
between nodes of Ranvier. In saltatory
impulse conduction, only the nodal
membrane is depolarized. Because depolarization
can still occur after blockade
of three or four nodal rings, the area
exposed to a drug concentration sufficient
to cause blockade must be larger
for motor fibers (p. 205B).
This relationship explains why sen sory
stimuli that are conducted via
myelinated A"-fibers are affected later
and to a lesser degree than are stimuli
conducted via unmyelinated C-fibers.
Since autonomic postganglionic fibers
lack a myelin sheath, they are particularly
susceptible to blockade by local
anesthetics. As a result, vasodilation ensues
in the anesthetized region, because
sympathetically driven vasomotor tone
decreases. This local vasodilation is undesirable.

Diffusion and Effect
During diffusion from the injection site
(i.e., the interstitial space of connective
tissue) to the axon of a sensory nerve,
the local anesthetic must traverse the
perineurium. The multilayered perineurium
is formed by connective tissue
cells linked by zonulae occludentes
and therefore constitutes a
closed lipophilic barrier.
Local anesthetics in clinical use are
usually tertiary amines; at the pH of
interstitial fluid, these exist partly as the
neutral lipophilic base (symbolized by
particles marked with two red dots) and
partly as the protonated form, i.e., amphiphilic
cation (symbolized by particles
marked with one blue and one red
dot). The uncharged form can penetrate
the perineurium and enters the endoneural
space, where a fraction of the
drug molecules regains a positive
charge in keeping with the local pH. The
same process is repeated when the drug
penetrates the axonal membrane (axolemma)
into the axoplasm, from which
it exerts its action on the sodium channel,
and again when it diffuses out of the
endoneural space through the unfenestrated
endothelium of capillaries into
the blood.
The concentration of local anesthetic
at the site of action is, therefore,
determined by the speed of penetration
into the endoneurium and the speed of
diffusion into the capillary blood. In order
to ensure a sufficiently fast build-up
of drug concentration at the site of action,
there must be a correspondingly
large concentration gradient between
drug depot in the connective tissue and
the endoneural space. Injection of solutions
of low concentration will fail to
produce an effect; however, too high
concentrations must also be avoided because
of the danger of intoxication resulting
from too rapid systemic absorption
into the blood.
To ensure a reasonably long-lasting
local effect with minimal systemic action,
a vasoconstrictor (epinephrine,
less frequently norepinephrine (p. 84)
or a vasopressin derivative; p. 164) is often
co-administered in an attempt to
confine the drug to its site of action. As
blood flow is diminished, diffusion from
the endoneural space into the capillary
blood decreases because the critical
concentration gradient between endoneural
space and blood quickly becomes
small when inflow of drug-free blood is
reduced. Addition of a vasoconstrictor,
moreover, helps to create a relative
ischemia in the surgical field. Potential
disadvantages of catecholamine-type
vasoconstrictors include reactive hyperemia
following washout of the constrictor
agent and cardiostimulation
when epinephrine enters the systemic
circulation. In lieu of epinephrine,
the vasopressin analogue felypressin
can be used as an adjunctive
vasoconstrictor (less pronounced
reactive hyperemia, no arrhythmogenic
action, but danger of coronary constriction).
Vasoconstrictors must not be applied
in local anesthesia involving the
appendages (e.g., fingers, toes).
Characteristics of chemical structure.
Local anesthetics possess a uniform
structure. Generally they are secondary
or tertiary amines. The nitrogen
is linked through an intermediary chain
to a lipophilic moiety—most often an
aromatic ring system.
The amine function means that local
anesthetics exist either as the neutral
amine or positively charged ammonium
cation, depending upon their dissociation
constant (pKa value) and the
actual pH value. The pKa of typical local
anesthetics lies between 7.5 and 9.0.
The pka indicates the pH value at which
50% of molecules carry a proton. In its
protonated form, the molecule possesses
both a polar hydrophilic moiety (protonated
nitrogen) and an apolar lipophilic
moiety (ring system)—it is amphiphilic.
Graphic images of the procaine
molecule reveal that the positive charge
does not have a punctate localization at
the N atom; rather it is distributed, as
shown by the potential on the van der
Waals’ surface. The non-protonated
form (right) possesses a negative partial
charge in the region of the ester bond
and at the amino group at the aromatic
ring and is neutral to slightly positively
charged (blue) elsewhere. In the protonated
form (left), the positive charge is
prominent and concentrated at the amino
group of the side chain (dark blue).
Depending on the pKa, 50 to 5% of
the drug may be present at physiological
pH in the uncharged lipophilic form.
This fraction is important because it
represents the lipid membrane-permeable
form of the local anesthetic,
which must take on its cationic amphiphilic
form in order to exert its action.
Clinically used local anesthetics are
either esters or amides. This structural
element is unimportant for efficacy;
even drugs containing a methylene
bridge, such as chlorpromazine
or imipramine, would exert a
local anesthetic effect with appropriate
application. Ester-type local anesthetics
are subject to inactivation by tissue esterases.
This is advantageous because of
the diminished danger of systemic intoxication.
On the other hand, the high
rate of bioinactivation and, therefore,
shortened duration of action is a disadvantage.
Procaine cannot be used as a surface
anesthetic because it is inactivated faster
than it can penetrate the dermis or
mucosa.
The amide type local anesthetic
lidocaine is broken down primarily in
the liver by oxidative N-dealkylation.
This step can occur only to a restricted
extent in prilocaine and articaine because
both carry a substituent on the Catom
adjacent to the nitrogen group. Articaine
possesses a carboxymethyl
group on its thiophen ring. At this position,
ester cleavage can occur, resulting
in the formation of a polar -COO– group,
loss of the amphiphilic character, and
conversion to an inactive metabolite.
Benzocaine (ethoform) is a member
of the group of local anesthetics lacking
a nitrogen that can be protonated at
physiological pH. It is used exclusively
as a surface anesthetic.
Other agents employed for surface
anesthesia include the uncharged polidocanol
and the catamphiphilic cocaine,
tetracaine, and lidocaine.